Chronic valproate administration produces hepatic dysfunction and may delay brain maturation in infant mice.
Infant mice (2 to 4 days old) received valproate (100 or 200 mg per kilogram body weight) subcutaneously once daily for 5 days. Both dosages decreased plasma beta-hydroxybutyrate levels to about one-third of the control value, in the face of normal free fatty acid and glycerol levels. At 200 mg per kilogram of valproate, there were significant decreases in brain weight and brain K content. Both doses produced metabolite changes in brain compatible with a reduced metabolic flux through the glycolytic pathway and the citric acid cycle. Valproate reduced brain aspartate but did not increase brain GABA levels in infant mice. At 200 mg per kilogram of valproate, brain glutamate decreased and taurine levels increased. Two hundred milligrams per kilogram of valproate caused a profound reduction of liver glycogen stores. The apparent decrease in cerebral metabolic rate, reduced glutamate and aspartate, and increased levels of taurine in brain may relate to the anticonvulsant action of valproate. Together with the decreased brain weight and K content, the findings are also compatible with maturational delay. Decreased ketonemia and liver glycogen content may relate to the hepatic toxicity associated with valproate administration in infants and children.
D020155:3-Hydroxybutyric Acid; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn / Q000378:metabolism*; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism*; D006885:Hydroxybutyrates / Q000097:blood; D008099:Liver / Q000378:metabolism*; D008112:Liver Glycogen / Q000378:metabolism; D051379:Mice; D009929:Organ Size / Q000187:drug effects; D014635:Valproic Acid / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology*
D000596:Amino Acids; D001786:Blood Glucose; D006885:Hydroxybutyrates; D008112:Liver Glycogen; D014635:Valproic Acid; D020155:3-Hydroxybutyric Acid